Lapatinib in Combination With Radiation Therapy in Patients With Brain Metastases From HER2-Positive Breast Cancer

• Sponsor: Nancy Lin, MD (Other)
• Overall Status: Completed
• CT.gov ID: NCT00470847
• Collaborator: Brigham and Women's Hospital (Other), Breast Cancer Research Foundation (Other), GlaxoSmithKline (Industry)
• Enrollment: 35
• Locations: 3
• Arm: 1
• Duration (Months): 62
• Patients Per Site: 11.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this research study is to determine the safety of combining lapatinib plus radiation in patients with breast cancer that has spread to the brain. Depending upon the participants cancer, they may also have stereotactic radiosurgery (SRS). Lapatinib s a compound that may stop cancer cells from growing abnormally. It is thought that lapatinib might also make cancer cells more sensitive to radiation. This drug has been used in other research studies in women with breast cancer, and information from those other research studies suggests that lapatinib may help to shrink or stabilize breast tumors both inside the brain and outside the brain.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer; Brain Metastases	Drug: Lapatinib; Procedure: Whole Brain Radiation; Drug: Herceptin	Phase 1

Detailed Description

• Participant's will be given a study medication-dosing calendar for each treatment cycle. Each treatment cycle lasts four weeks. On the first day of the treatment cycle, participants will take 1 lapatinib orally twice per day, 12 hours apart. After the first day, lapatinib will be taken once a day in the morning.

• Whole brain radiation treatments will begin approximately 1-8 days after the first dose of lapatinib. The radiation treatments will follow standard guidelines and will be supervised by a radiation oncologist. Radiation will be given in 15 treatments over a period of three weeks.

• Some participants will also undergo stereotactic radiosurgery (SRS). SRS is a highly focused and intense form of radiation treatment generally done as an outpatient procedure in a single treatment.

• After whole brain radiation treatments are completed, lapatinib will be continued at the same dose for one more week. After that, the lapatinib dose may change. In addition at the same time, Herceptin will be started. Participants will continue with both lapatinib and herceptin together as long as there is evidence that they are benefitting from it.

• During all treatment cycles participants will have a physical exam and be asked general questions about their health. Photographs will be taken of the tumor, if visible, to assess the response of the tumor to the treatment. An assessment of the tumor by CT scan of the body, and MRI imaging of the brain will be performed every two months. An assessment of heart function by MUGA scan or echocardiogram will be performed every 8 weeks. The participant will also be asked to complete a brief questionnaire measuring quality of life and asking about symptoms related to the cancer at baseline, 6 months, and one year. Blood tests will be performed every 4 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I Study of Lapatinib in Combination With Radiation Therapy in Patients With Brain Metastases From HER2-Positive Breast Cancer
• Study Start Date: Apr 1, 2007
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Other: Lapatinib,Whole Brain Radiation,Herceptin Lapatinib before and during Whole Brain Radiation Therapy (WBRT), then Herceptin 4mg/kg IV weekly	Drug: Lapatinib; Orally twice daily; Other Names: Tykerb ; Procedure: Whole Brain Radiation; 15 treatments over a period of 3 weeks; Drug: Herceptin; Herceptin 4mg/kg loading dose then 2 mg/kg IV once weekly, then once every three weeks after cycle 3.; Other Names: Trastuzumab

Outcome Measures

Primary Outcome Measures

1. The Maximum Tolerated Dose of Lapatinib When Combined With Cranial Radiation in Patients With CNS Metastases From HER2-positive Breast Cancer. [5 Years]

   The maximum tolerated dose is defined as :The highest dose of a drug or treatment that does not cause unacceptable side effects.

Secondary Outcome Measures

1. Progression Free Survival [5 years]

   Progression Free Survival is the time from date of start of treatment to the date of the first documented progression or death due to any cause. If a patient has not progressed or died, progression free survival is censored at the time of last tumor assessment. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0), as a 20 % increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

2. Objective Response Rate in Central Nervous System Sites [5 years]

   Objective Response Rate was defined using volumetric response as the following: Complete Response (CR) is the disappearance of all target lesions, stable/responsive non-target lesions, and no new lesions. Partial response (PR) is at least a 50% reduction in the sum of the target lesions, stable/responsive non-target lesions, and no new lesions. Stable Disease (SD) is neither CR PR or Progressive Disease (PD). And Progressive Disease (PD) is at least 40% increase in sum of target lesionsor the appearance of any new lesion >=6mm in the longest dimension. If a patient progressed in a non-central nervous system(CNS) site first, died, or withdrew from the study for any reason after the first dose of drug was administered, and before a CR or PR in the central nervous system was determined, she was considered a CNS non-responder.

3. Percentage of Participants Having Central Nervous System as the Site of the First Progression [5 years]

4. Percentage of Participants Having Non-Central Nervous System Sites as the Site of First Progression [5 years]

5. Overall Survival [Participants were followed for an average of 3.8 years]

   Overall average length of participant survival after protocol initiation

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically or cytologically-confirmed invasive breast cancer

• HER2 overexpressing breast cancer defined as 3+ staining by immunohistochemistry, or HER2 gene amplification by FISH

• At least one parenchymal brain metastasis

• Disease progression in the CNS as assessed by at least one of the following; new neurological signs or symptoms; new lesion(s) in the CNS on an imaging study; progressive lesions on an imaging study

• At least two weeks since prior radiotherapy, last chemotherapy, immunotherapy, biologic therapy, or major surgery for cancer

• 18 years of age or older

• Life expectancy of greater than 12 weeks

• ECOG performance status 0-2

• Normal organ and marrow function as described in the protocol

• Left ventricular ejection fraction > 50%

• Able to swallow and retain oral medications

Exclusion Criteria:

• Prior WBRT

• Receiving any other investigational agents

• Concurrent chemotherapy, immunotherapy, biologic therapy or hormonal therapy for treatment of their cancer

• History of grade 3 or 4 allergic reactions attributed to compounds of similar chemical or biologic composition to herceptin or lapatinib

• Leptomeningeal carcinomatosis as the only site of CNS involvement

• Concurrent treatment with medications that are either inducers of inhibitors of CYP3A4

• Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or active ulcerative colitis

• History of immediate or delayed hypersensitivity reaction to gadolinium contrast agents

• Other known contraindication to MRI

• Uncontrolled intercurrent illness

• History of other active malignancy except curatively treated basal cell carcinoma or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix

• Pregnant or breastfeeding women

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
2	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
3	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Nancy Lin, MD
• Brigham and Women's Hospital
• Breast Cancer Research Foundation
• GlaxoSmithKline

Investigators

• Principal Investigator: Nancy Lin, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Nancy Lin, MD, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT00470847
• Other Study ID Numbers: 06-356
• First Posted: May 8, 2007
• Last Update Posted: May 22, 2014
• Last Verified: Apr 1, 2014

• Keywords provided by Nancy Lin, MD, Principal Investigator, Dana-Farber Cancer Institute: Herceptin; breast cancer; radiation therapy; stereotactic radiosurgery; SRS; whole brain radiation; WBRT
• Additional relevant MeSH terms: Breast Neoplasms; Neoplasm Metastasis; Brain Neoplasms; Trastuzumab; Lapatinib

Study Results

Participant Flow

Recruitment Details	Participants were recruited between May 2007 and December 2009.

Arm/Group Title	Lapatinib,Whole Brain Radiation,Herceptin
Arm/Group Description	Participants received lapatinib, orally, 750mg twice on day one followed by 1000mg, 1250mg, or 1500mg once daily. Whole Brain Radiation therapy (WBRT) (37.5 Gy, 15 fractions) began 1-8 days after starting lapatinib. Lapatinib was continued through WBRT. Following WBRT, patients received trastuzumab intravenously 2mg/kg weekly and lapatinib 1000mg orally once daily.
Period Title: Overall Study
STARTED	35
COMPLETED	34
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Lapatinib,Whole Brain Radiation,Herceptin
Arm/Group Description	Lapatinib before and during Whole Brain Radiation Therapy (WBRT), then Herceptin 4mg/kg IV weekly
Overall Participants	35
Age, Customized (participants) [Number]
Between 30 and 78	35 100%
Sex: Female, Male (Count of Participants)
Female	35 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	35 100%

Outcome Measures

1. Primary Outcome

Title	The Maximum Tolerated Dose of Lapatinib When Combined With Cranial Radiation in Patients With CNS Metastases From HER2-positive Breast Cancer.
Description	The maximum tolerated dose is defined as :The highest dose of a drug or treatment that does not cause unacceptable side effects.
Time Frame	5 Years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lapatinib,Whole Brain Radiation,Herceptin
Arm/Group Description	Lapatinib before and during Whole Brain Radiation Therapy (WBRT), then Herceptin 4mg/kg IV weekly
Measure Participants	35
Number [milligrams]	1250

2. Secondary Outcome

Title	Progression Free Survival
Description	Progression Free Survival is the time from date of start of treatment to the date of the first documented progression or death due to any cause. If a patient has not progressed or died, progression free survival is censored at the time of last tumor assessment. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0), as a 20 % increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lapatinib,Whole Brain Radiation,Herceptin
Arm/Group Description	Lapatinib before and during Whole Brain Radiation Therapy (WBRT), then Herceptin 4mg/kg IV weekly
Measure Participants	35
Median (Full Range) [months]	4.8

3. Secondary Outcome

Title	Objective Response Rate in Central Nervous System Sites
Description	Objective Response Rate was defined using volumetric response as the following: Complete Response (CR) is the disappearance of all target lesions, stable/responsive non-target lesions, and no new lesions. Partial response (PR) is at least a 50% reduction in the sum of the target lesions, stable/responsive non-target lesions, and no new lesions. Stable Disease (SD) is neither CR PR or Progressive Disease (PD). And Progressive Disease (PD) is at least 40% increase in sum of target lesionsor the appearance of any new lesion >=6mm in the longest dimension. If a patient progressed in a non-central nervous system(CNS) site first, died, or withdrew from the study for any reason after the first dose of drug was administered, and before a CR or PR in the central nervous system was determined, she was considered a CNS non-responder.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

28 participants had measurable disease out of the 35 participants enrolled.

Arm/Group Title	Lapatinib,Whole Brain Radiation,Herceptin
Arm/Group Description	Lapatinib before and during Whole Brain Radiation Therapy (WBRT), then Herceptin 4mg/kg IV weekly
Measure Participants	28
Number (95% Confidence Interval) [percentage of participants]	79 225.7%

4. Secondary Outcome

Title	Percentage of Participants Having Central Nervous System as the Site of the First Progression
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lapatinib,Whole Brain Radiation,Herceptin
Arm/Group Description	Lapatinib before and during Whole Brain Radiation Therapy (WBRT), then Herceptin 4mg/kg IV weekly
Measure Participants	35
Number [percentage of participants]	23 65.7%

5. Secondary Outcome

Title	Percentage of Participants Having Non-Central Nervous System Sites as the Site of First Progression
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lapatinib,Whole Brain Radiation,Herceptin
Arm/Group Description	Lapatinib before and during Whole Brain Radiation Therapy (WBRT), then Herceptin 4mg/kg IV weekly
Measure Participants	35
Number [percentage of participants]	46 131.4%

6. Secondary Outcome

Title	Overall Survival
Description	Overall average length of participant survival after protocol initiation
Time Frame	Participants were followed for an average of 3.8 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lapatinib,Whole Brain Radiation,Herceptin
Arm/Group Description	Lapatinib before and during Whole Brain Radiation Therapy (WBRT), then Herceptin 4mg/kg IV weekly
Measure Participants	35
Median (Full Range) [Months]	19

Adverse Events

Time Frame	May 2007- December 2009
Adverse Event Reporting Description	Serious Adverse Events include all Participants N=35. Non-serious Adverse Events also include all participants N=35.
Arm/Group Title	Dose Level 2		Dose Level 1		Dose Level 3
Arm/Group Description	n=27 participants Maximum Tolerated Dose 1250 mg lapatinib daily		n=3 participants 1000 mg lapatinib daily		n=5 participants 1500 mg lapatinib daily
All Cause Mortality
	Dose Level 2		Dose Level 1		Dose Level 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Dose Level 2		Dose Level 1		Dose Level 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/27 (29.6%)		0/3 (0%)		0/5 (0%)
Gastrointestinal disorders
Diarrhea	2/27 (7.4%)	2	0/3 (0%)	0	0/5 (0%)	0
Vomiting	2/27 (7.4%)	2	0/3 (0%)	0	0/5 (0%)	0
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/27 (3.7%)	1	0/3 (0%)	0	0/5 (0%)	0
Sinusitis	1/27 (3.7%)	1	0/3 (0%)	0	0/5 (0%)	0
Pulmonary Embolus	2/27 (7.4%)	2	0/3 (0%)	0	0/5 (0%)	0
Other (Not Including Serious) Adverse Events
	Dose Level 2		Dose Level 1		Dose Level 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/27 (100%)		3/3 (100%)		5/5 (100%)
Blood and lymphatic system disorders
Hemoglobin	9/27 (33.3%)	9	1/3 (33.3%)	1	3/5 (60%)	3
Lymphocytes/leukocytes	11/27 (40.7%)	11	2/3 (66.7%)	2	3/5 (60%)	3
Platelets	6/27 (22.2%)	6	0/3 (0%)	0	0/5 (0%)	0
Neutrophils	3/27 (11.1%)	3	1/3 (33.3%)	1	2/5 (40%)	2
Endocrine disorders
Hyperglycemia	10/27 (37%)	10	2/3 (66.7%)	2	3/5 (60%)	3
Eye disorders
Ocular	3/27 (11.1%)	3	1/3 (33.3%)	1	2/5 (40%)	2
Gastrointestinal disorders
Diarrhea	21/27 (77.8%)	21	3/3 (100%)	3	4/5 (80%)	4
Dyspepsia	4/27 (14.8%)	4	0/3 (0%)	0	0/5 (0%)	0
Nausea	18/27 (66.7%)	18	2/3 (66.7%)	2	4/5 (80%)	4
Vomiting	14/27 (51.9%)	14	2/3 (66.7%)	2	2/5 (40%)	2
Constipation	7/27 (25.9%)	7	0/3 (0%)	0	1/5 (20%)	1
Anorexia	14/27 (51.9%)	14	0/3 (0%)	0	2/5 (40%)	2
Pain-abdominal	3/27 (11.1%)	3	0/3 (0%)	0	2/5 (40%)	2
General disorders
Dehydration	7/27 (25.9%)	7	0/3 (0%)	0	1/5 (20%)	1
Insomnia	4/27 (14.8%)	4	0/3 (0%)	0	2/5 (40%)	2
Fatigue	21/27 (77.8%)	21	3/3 (100%)	3	5/5 (100%)	5
Hepatobiliary disorders
AST/ALT alkaline phosphatase	13/27 (48.1%)	13	2/3 (66.7%)	2	3/5 (60%)	3
Bilirubin	2/27 (7.4%)	2	1/3 (33.3%)	1	1/5 (20%)	1
Infections and infestations
Mucositis/chelitis	5/27 (18.5%)	5	0/3 (0%)	0	2/5 (40%)	2
Infection	10/27 (37%)	10	1/3 (33.3%)	1	2/5 (40%)	2
Metabolism and nutrition disorders
Hypoalbuminemia	9/27 (33.3%)	9	0/3 (0%)	0	0/5 (0%)	0
Hypocalcemia	6/27 (22.2%)	6	0/3 (0%)	0	1/5 (20%)	1
Hypokalemia	8/27 (29.6%)	8	0/3 (0%)	0	1/5 (20%)	1
Hyperkalemia	2/27 (7.4%)	2	1/3 (33.3%)	1	0/5 (0%)	0
Hyponatremia	6/27 (22.2%)	6	0/3 (0%)	0	2/5 (40%)	2
Musculoskeletal and connective tissue disorders
Weakness	3/27 (11.1%)	3	0/3 (0%)	0	0/5 (0%)	0
Pain-back	5/27 (18.5%)	5	0/3 (0%)	0	1/5 (20%)	1
Limb, joint, other pain	6/27 (22.2%)	6	0/3 (0%)	0	2/5 (40%)	2
Nervous system disorders
Headache	14/27 (51.9%)	14	1/3 (33.3%)	1	2/5 (40%)	2
Neuropathy-face-motor/taste	3/27 (11.1%)	3	1/3 (33.3%)	1	0/5 (0%)	0
Neuropathy-Sensory	7/27 (25.9%)	7	0/3 (0%)	0	2/5 (40%)	2
Neuropathy motor or neurologic-other	8/27 (29.6%)	8	0/3 (0%)	0	2/5 (40%)	2
Dizziness	4/27 (14.8%)	4	0/3 (0%)	0	4/5 (80%)	4
Memory Impairment	4/27 (14.8%)	4	0/3 (0%)	0	1/5 (20%)	1
Seizure	0/27 (0%)	0	0/3 (0%)	0	1/5 (20%)	1
Psychiatric disorders
Depression	4/27 (14.8%)	4	0/3 (0%)	0	0/5 (0%)	0
Renal and urinary disorders
Kidney function/proteinuria	3/27 (11.1%)	3	1/3 (33.3%)	1	0/5 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary/Upper respiratory/cough	9/27 (33.3%)	9	0/3 (0%)	0	3/5 (60%)	3
Skin and subcutaneous tissue disorders
Dry Skin	4/27 (14.8%)	4	0/3 (0%)	0	0/5 (0%)	0
Pruritis	7/27 (25.9%)	7	0/3 (0%)	0	3/5 (60%)	3
Radiation dermatitis	9/27 (33.3%)	9	1/3 (33.3%)	1	4/5 (80%)	4
Rash-Acneiform	16/27 (59.3%)	16	2/3 (66.7%)	2	3/5 (60%)	3
Alopecia	5/27 (18.5%)	5	1/3 (33.3%)	1	1/5 (20%)	1
Vascular disorders
Hypertension	3/27 (11.1%)	3	1/3 (33.3%)	1	0/5 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.